Abstract Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy. Current treatments for CIDP are non-specific, ineffective in one-third of patients, and do not result in complete remission in most patients. Thus, more effective, mechanism-based therapies are needed, and understanding the immune tolerance defects that result in PNS autoimmunity will enable their development. Studies to date suggest a model in which CD4+ T cells, macrophages, and complement lead to the autoimmune destruction of Schwann cells in the PNS. Our data indicate that Schwann cells unexpectedly undergo changes during autoimmune attack that may expand the inflammatory response. Schwann cells turn on expression of Periostin, a secreted extracellular matrix protein important in chemotaxis of pathogenic macrophages; increase expression of CD49b, an integrin important in binding complement protein C1q; and induce expression of MHC Class II, a molecule required for antigen-presentation to CD4+ T cells. Thus, we hypothesize that Schwann cell-associated changes may promote autoimmunity through increased macrophage recruitment, complement deposition, and CD4+ T cell activation. To test this, we propose to determine whether: i) Schwann cell-specific Periostin expression is sufficient to drive macrophage recruitment and neuropathy development; ii) loss of CD49b in Schwann cells and/or C1q prevents complement activation and protects from neuropathy; and iii) Schwann cell-specific MHCII deficiency dampens CD4+ T cell stimulation and protects against PNS autoimmunity. These Aims will be tested in CIDP mouse models and patient nerve biopsies. This project takes advantage of complementary expertise of the multiple PI's (Dr. Su in PNS autoimmunity and Dr. Scherer in Schwann cell biology) to elucidate the role of Schwann cells in promoting demyelinating neuropathy. Successful completion of the Aims of this project will pave the way to identifying new targets for mechanism-based immunotherapeutic interventions for CIDP. Additionally, findings from these studies will contribute to a broader understanding of how Schwann cells may amplify inflammation in immune- mediated diseases of the PNS.